Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
Asthma is a heterogeneous and multifactorial disease that manifests as episodes of wheezing, coughing and shortness of breath. Both family-based and twin studies indicate that asthma is a complex genetic disorder1. Multiple genetic and environmental factors are also known to modulate the clinical expression of the disease and its associated phenotypes, bronchial hyper-responsiveness, atopy, and elevated IgE2,3. In a recent GWA study, a single locus harboring ORMDL3 on 17q12-q21 was found to associate with asthma contributing modestly to disease risk, thereby notably reducing the possibility of the presence of common variants with large effect size in asthma6. However, as only a small proportion of the disease heritability has been explained to date, it follows that additional high frequency variants of modest risk remain to be uncovered. The identification of further genetic predisposition loci may lead to improved understanding of the biological basis of the disease and potentially also serve as new therapeutic targets.
GWA has proven to be a robust approach to gene variant discovery in complex disease7. However, unlike type 2 diabetes or inflammatory bowel disease (IBD) where multiple variants underlying the genetic susceptibility to these conditions have been discovered8,9, only a single locus has thus far been shown to associate with asthma predisposition through GWA6. This suggests that either substantially larger numbers of subjects need to be studied, as with type 2 diabetes and IBD, or the sample must be enriched for genetic disease by sampling for lower age of onset or increased disease severity. Age of onset is one of the most easily tractable asthma phenotypes and, as longitudinal studies have established, strongly correlated with a number of other asthma phenotypes4,5.
Clearly a need exists to identify other genes involved in the manifestation of the asthmatic phenotype, particularly pediatric onset asthma. Such knowledge will facilitate diagnosis of this condition as well as provide new targets for the development of potent therapeutics for the treatment of asthma.